CaMKIIα enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism

Sessoms-Sikes, Suzanne; Honse, Yumiko; Lovinger, David M.; Colbran, Roger J.

doi:10.1016/j.mcn.2005.01.006

Cited by 68 publications

(47 citation statements)

References 48 publications

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“…This model raises the question whether CaMKII binding to NR1 C0 per se affects desensitization. In fact, ectopic co-expression of NR1 and NR2A with CaMKII in the non-neuronal HEK293 cell line leads to decreased desensitization as compared to NR1/NR2A only expression (59). These results would be consistent with the possibility that CaMKII binding to NR1 C0 reduces the desensitization that occurs when α-actinin is displaced by Ca 2+ /CaM from NR1 C0 (28,29).…”

Section: Discussionsupporting

confidence: 64%

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca²⁺/Calmodulin Promotes CaMKII Binding

et al. 2007

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Ca 2+ influx through the N-methyl-D-aspartate (NMDA)-type glutamate receptor triggers activation and postsynaptic accumulation of Ca 2+ /calmodulin-dependent kinase II (CaMKII). CaMKII, calmodulin, and α-actinin directly bind to the short membrane proximal C0 domain of the C-terminal region of the NMDA receptor NR1 subunit. In a negative feedback loop, calmodulin mediates Ca 2+ -dependent inactivation of the NMDA receptor by displacing α-actinin from NR1 C0 upon Ca 2+ influx. We show that Ca 2+ -depleted calmodulin and α-actinin simultaneously bind to NR1 C0. Upon addition of Ca 2+ , calmodulin dislodges α-actinin. Either the N-or C-terminal half of calmodulin is sufficient for Ca 2+ -induced displacement of α-actinin. While α-actinin directly antagonizes CaMKII binding to NR1 C0, the addition of Ca 2+ /calmodulin shifts binding of NR1 C0 toward CaMKII by displacing α-actinin. Displacement of α-actinin results in the simultaneous binding of calmodulin and CaMKII to NR1 C0. Our results reveal an intricate mechanism whereby Ca 2+ functions to govern the complex interactions between the two most prevalent signaling molecules in synaptic plasticity, the NMDA receptor and CaMKII.N-methyl-D-aspartate (NMDA) receptors mediate Ca 2+ influx at the postsynaptic site leading to the activation of Ca 2+ /calmodulin-dependent kinase II (CaMKII) by Ca 2+ /calmodulin (CaM) (1). CaMKII regulates various neuronal functions including ion-channel activity, neuronal excitability, and gene expression. Ca 2+ influx through the NMDA receptor and subsequent activation of CaMKII are the key signaling steps in learning and memory and in longterm potentiation (LTP), which is thought to underlie memory formation (2-5). Activation of CaMKII by Ca 2+ /CaM and the ensuing Thr 286 autophosphorylation promotes CaMKII binding to several postsynaptic proteins including the NR1 (6,7), NR2A (8,9), and NR2B subunits (6,(10)(11)(12)(13)(14) of the NMDA receptor (for review see (15,16)). CaMKII consists of 12 homologous subunits. Targeting stimulated CaMKII to the NMDA receptor would allow for fast and effective activation of additional subunits in the dodecameric CaMKII complex by NMDA receptor mediated Ca 2+ influx. It also promotes specific and efficient phosphorylation of NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript neighboring postsynaptic targets including α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors (6,(17)(18)(19).The NMDA receptor is likely a tetramer consisting of two obligatory NR1 subunits and two NR2 (A-D) subunits (20)(21)(22)(23). The cytosolic C-terminus of NR1 binds several postsynaptic proteins including CaM (24), α-actinin (25) and CaMKII (6,7). High affinity binding of CaMKII to NR1 requires autophosphorylation of Thr 286 (7). Using peptide libraries of the Cterminal portion of NR1, we determined the amino acid sequence responsible for CaMKII, CaM and α-actinin binding to NR1 (7). All three proteins bind to residues 845-863 of the membrane-proximal C0 reg...

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Section: Discussionsupporting

confidence: 64%

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca²⁺/Calmodulin Promotes CaMKII Binding

et al. 2007

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“…3b). It is possible that inhibition of CaMKII could alter NMDAR function and/or trafficking (Sessoms-Sikes et al, 2005;Mauceri et al, 2007) and in this way prevent NMDA-mediated mIPSC potentiation. However, because the extent of membrane depolarization recorded during NMDA treatment was unaffected by AIP, we find this explanation unlikely.…”

Section: Discussionmentioning

confidence: 99%

NMDA Receptor Activation Potentiates Inhibitory Transmission through GABA Receptor-Associated Protein-Dependent Exocytosis of GABA_AReceptors

Marsden¹,

Beattie²,

Friedenthal³

et al. 2007

J. Neurosci.

168

203

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The trafficking of postsynaptic AMPA receptors (AMPARs) is a powerful mechanism for regulating the strength of excitatory synapses. It has become clear that the surface levels of inhibitory GABA A receptors (GABA A Rs) are also subject to regulation and that GABA A R trafficking may contribute to inhibitory plasticity, although the underlying mechanisms are not fully understood. Here, we report that NMDA receptor activation, which has been shown to drive excitatory long-term depression through AMPAR endocytosis, simultaneously increases

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“…Local NMDAR-mediated Ca 2ϩ influx might promote sequential CaMKII dissociation from ␣-actinin, activation/autophosphorylation, and binding to NR2B. Such events may play a role in the NR2 subunit-selective modulation of NMDAR desensitization (49). Additional experiments must be designed to test various aspects of these models.…”

Section: Discussionmentioning

confidence: 99%

Differential Modulation of Ca2+/Calmodulin-dependent Protein Kinase II Activity by Regulated Interactions with N-Methyl-D-aspartate Receptor NR2B Subunits and α-Actinin

Robison¹,

Bartlett²,

Bass

et al. 2005

Journal of Biological Chemistry

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Postsynaptic roles of CaMKII␣ in synaptic plasticity are thought to require specific targeting to the postsynaptic density (PSD), a cytoskeletal structure juxtaposed to excitatory synapses that is enriched in neurotransmitter receptors and other signaling proteins. Immunohistochemical studies have revealed a wide range in the amount of CaMKII associated with individual PSDs (4, 5), consistent with a dynamic regulation of PSD targeting. Exogenous, Thr 286 -autophosphorylated CaMKII␣ ([P-T 286 ]CaMKII) binds specifically to isolated PSDs (6). Moreover, pharmacological treatments of hippocampal slices that activate CaMKII and induce long term potentiation, a form of synaptic plasticity, increase the amount of CaMKII associated with PSD-enriched subcellular fractions (6). Elegant studies of green fluorescent protein-CaMKII localization in cultured hippocampal neurons suggest that transient translocation of soluble CaMKII␣ to synapses in response to NMDA-type glutamate receptor (NMDAR) activation requires only Ca 2ϩ /calmodulin binding to CaMKII (7). However, mutagenesis studies indicate that Thr 286 autophosphorylation stabilizes the synaptic targeting of green fluorescent protein-CaMKII␣, whereas Thr 305/306 autophosphorylation promotes dissociation of synaptic green fluorescent protein-CaMKII␣ (8). Consistent with these data, the transgenic mouse knock-in mutation of Thr 305 in CaMKII␣ to Asp shows reduced CaMKII association with the PSD and changes in long term potentiation and learning and memory (2, 9, 10). Interestingly, a mouse model of Angelman mental retardation syndrome that has deficits in long term potentiation and spatial learning also displays decreased PSD-associated CaMKII␣ and increased autophosphorylation at Thr 305/306 (11). Other studies have shown that PKC activation can also drive synaptic translocation of CaMKII by a mechanism that is dependent on the actin cytoskeleton (12). In combination, these studies suggest that multiple, complex cellular mechanisms control PSD targeting of CaMKII. However, the molecular basis for these dynamic interactions is poorly defined.CaMKII binds several PSD-enriched CaMKII-associated proteins (CaMKAPs), including F-actin (13), cyclin-dependent protein kinase 5 (14), synGAP␤ (15), ␣-actinin (14, 16), densin-180 (16, 17), and multiple NMDAR subunits (18 -21

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CaMKIIα enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism

Cited by 68 publications

References 48 publications

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca²⁺/Calmodulin Promotes CaMKII Binding

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca²⁺/Calmodulin Promotes CaMKII Binding

NMDA Receptor Activation Potentiates Inhibitory Transmission through GABA Receptor-Associated Protein-Dependent Exocytosis of GABA_AReceptors

Differential Modulation of Ca2+/Calmodulin-dependent Protein Kinase II Activity by Regulated Interactions with N-Methyl-D-aspartate Receptor NR2B Subunits and α-Actinin

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CaMKIIα enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism

Cited by 68 publications

References 48 publications

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca2+/Calmodulin Promotes CaMKII Binding

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca2+/Calmodulin Promotes CaMKII Binding

NMDA Receptor Activation Potentiates Inhibitory Transmission through GABA Receptor-Associated Protein-Dependent Exocytosis of GABAAReceptors

Differential Modulation of Ca2+/Calmodulin-dependent Protein Kinase II Activity by Regulated Interactions with N-Methyl-D-aspartate Receptor NR2B Subunits and α-Actinin

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Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca²⁺/Calmodulin Promotes CaMKII Binding

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca²⁺/Calmodulin Promotes CaMKII Binding

NMDA Receptor Activation Potentiates Inhibitory Transmission through GABA Receptor-Associated Protein-Dependent Exocytosis of GABA_AReceptors